The catalytic mechanisms and substrate specificities of decarboxylating dehydrogenases are under investigation. The structure of a closed, NAD- bound form of the decarboxylating dehydrogenase isopropylmalate dehydrogenase (IMDH) has been determined at 2.5 angstroms resolution by molecular replacement. This structure provides a basis for determining the origins of diverging substrate specificities among the decarboxylating dehydrogenases. Crystals have been obtained of a mutant IMDH whose substrate specificity has been altered to resemble that of isocitrate dehydrogenase (IDH). Crystals of pig heart isocitrate dehydrogenase have also been obtained.